Macrophages and lymphocytes play a central role in inflammatory reactions in response to foreign or infectious agents. Monocytes are first chemotactically attracted to the injured tissue in which they differentiate structurally and functionally into tissue specific macrophages. Via the expression of specific receptors and the release of appropriate cytokines, macrophages govern and coordinate in a well ordered series of cellular mediated events the inflammatory reaction which eventually leads to the eradication of the intruder and the repair of the damaged tissue. When inflammation persists and becomes chronic, macrophages that have been accumulating fuse to form multinucleated giant cells onto the foreign substrate Although these giant macrophages appear to be actively involved in tumor defense mechanisms and bone resorption (where they are called osteoclasts), the functional relevance of their multinucleation remains highly speculative. Earlier reports indicate that giant cells can phagocytose as effectively as macrophages through a variety of receptors. This suggests that macrophages and giant cells share functional components and are equally capable of participating in host defense mechanisms. It has previously been shown that giant cells, whether elicited in vivo or in vitro are, like osteoclasts, polarized and express antigens that are not detected in mononucleated macrophages. To further investigate the role played by giant cells in chronic inflammatory reactions and to elucidate the putative interactions between giant cells and/or osteoclasts and the surrounding immune and nonimmune cells, the level of release of two cytokines, IL-1 and IL-6, by macrophages was compared to that of multinucleated giant cells. Because osteoclast activity is strongly inhibited by CT, the effect of this hormone was investigated to determine whether it could alter the level of release of these cytokines by multinucleated macrophages. This investigation demonstrated that giant cells, like peritoneal macrophages, do release spontaneously detectable levels of both IL-1 and IL-6; that CT is a weak inhibitor of IL-1 release but is specific for giant cells; that CGRP, a neuropeptide encoded by the same gene as CT, specifically blocks the release of IL-1 in both peritoneal macrophages and multinucleated giant cells; and that this inhibitory action of CGRP is mediated by intracellular cyclic adenosine monophosphate (cAMP) dependent mechanism. This work also demonstrates that CGRP directly alters the pattern of cytokine release by lymphocytes and has a profound effect on cytokine releasing cells (keratinocytes, mesangial cells, glial cells, etc.).
In a recently published paper, Nong, Yu-Hua et al., J. Immun., 143, 45-49, No. 1, pp. 45-49 (Jul. 1, 1989), report that CGRP profoundly inhibit the ability of macrophages to produce H.sub.2 O.sub.2 in response to IFN or to act as APC and that CT also prevented macrophage activation, suggesting to the authors that CGRP and CT play an important role in modulating the ability of macrophages to present Ag and to respond to activating factors.